The present invention is concerned with water soluble azoles as broad-spectum antifungals and their preparation; it further relates to compositions comprising them, as well as their use as a medicine.
Systemic fungal infections in man are relatively rare in temperate countries and many of the fungi that can become pathogenic normally live commensally in the body or are common in the environment. The past few decades have witnessed an increasing incidence of numerous life-threatening systemic fungal infections world-wide and these now represent a major threat to many susceptible patients, particularly those already hospitalized. Most of the increase can be attributed to improved survival of immunocompromised patients and the chronic use of antimicrobial agents. Moreover, the flora typical of many common fungal infections is also changing and this is presenting an epidemiological challenge of increasing importance. Patients at greatest risk include those with impaired immune functioning, either directly as a result of immunosuppression from cytotoxic drugs or HIV infection, or secondary to other debilitating diseases such as cancer, acute leukaemia, invasive surgical techniques or prolonged exposure to antimicrobial agents. The most common systemic fungal infections in man are candidosis, aspergillosis, histoplasmosis, coccidioidomycosis, paracoccidioidomycosis, blastomycosis and cryptococcosis.
Antifungals such as ketoconazole, itraconazole and fluconazole are employed for the treatment and prophylaxis of systemic fungal infections in immunocompromised patients. However, concern is growing about fungal resistance to some of these agents, especially these with a relatively narrow spectrum, e.g. fluconazole. Worse still, it is recognized in the medical world that about 40% of the people suffering from severe systemic fungal infections are hardly, or not at all, able to receive medication via oral administration. This inability is due to the fact that such patients are in coma or suffer from severe gastroparesis. Hence, the use of insoluble or sparingly soluble antifungals such as itraconazole, that are difficult to administer intravenously, is heavily impeded in this group of patients.
Also the treatment of onychomycosis may well be served by potent water soluble antifungals. It is long desired to treat onychomycosis via the transungual route. The problem that then arises is to ensure that the antifungal agents will penetrate into and beneath the nail. Mertin and Lippold (J. Pharm. Pharmacol. (1997), 49, 30-34) stated that in order to screen for drugs for topical application to the nail plate, attention has to be paid mainly to the water solubility of the compound. The maximum flux through the nail is beneficially influenced by increasing the water solubility of the antifungal. Of course, efficacy in treating onychomycosis via the transungual route is also dependent on the potency of the antifungal.
Consequently, there is a need for new antifungals, preferably broad-spectrum antifungals, against which there is no existing resistance and which can be administered intravenously or transungually. Preferably the antifungal should also be available in a pharmaceutical composition suitable for oral administration. This enables the physician to continue treatment with the same drug after the patient has recovered from the condition which required intravenous or transungual administration of said drug.
U.S. Pat. No. 4,267,179 discloses heterocyclic derivatives of (4-phenylpiperazin-1-yl-aryloxymethyl-1,3-dioxolan-2-yl)-methyl-1H-imidazoles and 1H-1,2,4-triazoles useful as antifungal agents. Said patent encompasses itraconazole, which is available as a broad-spectrum antifungal on a world-wide basis.
WO 93/19061 discloses the [2R-[2xcex1,4xcex1,4(R*)]], [2R-[2xcex1,4xcex1,4(S*)]], [2S-[2xcex1,4xcex1,4(S*)]] and [2S-[2xcex1,4xcex1,4(R*)]] stereospecific isomers of itraconazole, which are taught to have greater water solubility than the respective diastereomeric mixtures thereof.
WO 95/19983 discloses derivatives of [[4-[4-(4-phenyl-1-piperazinyl)phenoxymethyl]-1,3-dioxolan-2-yl]methyl]-1H-imidazoles and 1H-1,2,4-triazoles, structurally related to some of the compounds of the present invention, which are taught to be water-soluble antimicrobial agents.
WO 95/17407 discloses tetrahydrofuran antifungals as well as WO 96/38443 and WO 97/00255. The latter two publications disclose tetrahydrofuran antifungals, which are taught to be soluble and/or suspensible in an aqueous medium suitable for intravenous administration, containing substitution groups readily convertible in vivo into hydroxy groups.
Saksena et al. in Bioorganic and Medicinal Chemistry Letters (1995), 5(2), 127-132, discloses some tetrahydrofuran based azole antifungals such as (3R-cis)-4-[4-[4-[4-[[5-(2,4-difluorophenyl)tetrahydro-5-(1H-1,2,4-triazol-1-ylmethyl)-3-furanyl]methoxy]phenyl]-1-piperazinyl]phenyl]-2-[2-(dimethylamino)ethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one. Saksena et al. reported of said azole that, when compared to SCH 51048, it was profoundly less active as antifungal.
Unexpectedly, the compounds of the present invention are potent broad-spectrum antifungals with good water solubility.
The present invention concerns compounds of formula 
the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof, wherein
L represents a radical of formula 
xe2x80x83wherein
each Alk independently represents C1-6alkanediyl optionally substituted with hydroxy or C1-4alkyloxy;
each n independently is 1, 2 or 3;
Y represents O, S or NR2;
each R1 independently represents hydrogen, aryl, Het1, or C1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, mercapto, C1-4alkyloxy, C1-4alkylthio, aryloxy, arylthio, arylC1-4alkyloxy, arylC1-4alkylthio, cyano, amino, mono- or di(C1-4alkyl)amino, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, C1-4alkyloxycarbonylamino, benzyloxycarbonylamino, aminocarbonyl, carboxyl, C1-4alkyloxycarbonyl, guanidinyl, aryl or Het2;
each R2 independently represents hydrogen or C1-6alkyl; or
in case R1 and R2 are attached to the same nitrogen atom, they may be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl, homopiperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C1-4alkyl, aryl, Het2, arylC1-4alkyl, Het2C1-4alkyl, hydroxyC1-4alkyl, amino, mono- or di(C1-4alkyl)amino, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, carboxyl, aminocarbonyl, C1-4alkyloxycarbonyl, C1-4alkyloxycarbonylamino or mono- or di(C1-4alkyl)aminocarbonyl; or they may be taken together to form an azido radical;
each R3 independently represents hydrogen, hydroxy or C1-4alkyloxy;
aryl represents phenyl, naphthalenyl, 1,2,3,4-tetrahydro-naphthalenyl, indenyl or indanyl; each of said aryl groups may optionally be substituted with one or more substituents selected from halo, C1-4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl;
Het1 represents a monocyclic or bicyclic heterocyclic radical; said monocyclic heterocyclic radical being selected from the group pyridinyl, piperidinyl, homopiperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, triazolyl, pyranyl, tetrahydropyranyl, imidazolyl, imidazolinyl, imidazolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, thiazolyl, thiazolidinyl, isothiazolyl, oxazolyl, oxazolidinyl, isoxazolyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, furanyl, tetrahydrofuranyl, thienyl, thiolanyl, dioxolanyl; said bicyclic heterocyclic radical being selected from the group quinolinyl, 1,2,3,4-tetra-hydro-quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phtalazinyl, cinnolinyl, chromanyl, thiochromanyl, 2H-chromenyl, 1,4-benzodioxanyl, indolyl, isoindolyl, indolinyl, indazolyl, purinyl, pyrrolopyridinyl, furanopyridinyl, thienopyridinyl, benzothiazolyl, benzoxazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, benzofuranyl, benzothienyl; whereby each of said mono- or bicyclic heterocycle may optionally be substituted with one or where possible more substituents selected from halo, C1-4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, hydroxyC1-4alkyl, C1-4alkyloxy-C1-4alkyl, aminoC1-4alkyl, mono- or di(C1-4alkyl)aminoC1-4alkyl, aryl or arylC1-4alkyl;
Het2 is the same as Het1 and may also be a monocyclic heterocycle selected from piperazinyl, homopiperazinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl; whereby each of said monocyclic heterocycle may optionally be substituted with one or where possible more substituents selected from halo, C1-4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, aminoC1-4alkyl, mono- or di-(C1-4alkyl)aminoC1-4alkyl, aryl or arylC1-4alkyl;
R6 represents hydrogen or C1-4alkyl;
R7 represents hydrogen or C1-4alkyl; or
R6 and R7 taken together form a bivalent radical of formula xe2x80x94R6xe2x80x94R7xe2x80x94 wherein xe2x80x94R6xe2x80x94R7xe2x80x94 is:
xe2x80x83wherein one hydrogen atom in the radicals (i) and (ii) may be replaced with a C1-4alkyl radical and one or more hydrogen atoms in radicals (iii) and (iv) may be replaced by a C1-4alkyl radical;
D represents a radical of formula 
xe2x80x83wherein
X is N or CH;
R is hydrogen or halo;
R5 is halo.
As used in the foregoing definitions and hereinafter halo defines fluoro, chloro, bromo and iodo; C1-4alkyl encompasses the straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms such as, for example, methyl, ethyl, propyl, butyl and the like; C1-6alkyl encompasses the straight and branched chained saturated hydrocarbon radicals as defined in C1-4alkyl as well as the higher homologues thereof containing 5 or 6 carbon atoms such as, for example, pentyl or hexyl; C1-6alkanediyl encompasses the straight and branched chained saturated bivalent hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, 1,2thanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,2-propanediyl, 1,2-butanediyl, 2,3-butanediyl and the like.
The pharmaceutically acceptable addition salts as mentioned hereinabove are meant to comprise the therapeutically active non-toxic acid addition salt forms which the compounds of formula (I) are able to form. The latter can conveniently be obtained by treating the base form with such appropriate acids as inorganic acids, for example, hydrohalic acids, e.g. hydrochloric, hydrobromic and the like; sulfuric acid; nitric acid; phosphoric acid and the like; or organic acids, for example, acetic, propanoic, hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic, 2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids. Conversely the salt form can be converted by treatment with alkali into the free base form.
The compounds of formula (I) containing acidic protons may be converted into their therapeutically active non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases. Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)-1,3-propanediol, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely the salt form can be converted by treatment with acid into the free acid form.
The term addition salt also comprises the hydrates and solvent addition forms which the compounds of formula (I) are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like.
The term xe2x80x9cstereochemically isomeric formsxe2x80x9d as used hereinbefore defines all the possible stereoisomeric forms in which the compounds of formula (I) exist, thus, also including all enantiomers, enantiomeric mixtures and diastereomeric mixtures. Unless otherwise mentioned or indicated, the chemical designation of compounds denotes the mixture of all possible stereoisomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. The same applies to the intermediates as described herein, used to prepare end products of formula (I).
Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term xe2x80x98stereoisomerically purexe2x80x99 being equivalent to xe2x80x98chirally purexe2x80x99 concerns compounds or intermediates having a stereoisomeric excess of at least 80% (ie. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms xe2x80x98enantiomerically purexe2x80x99 and xe2x80x98diastereomerically purexe2x80x99 should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question.
The terms cis and trans are used herein in accordance with Chemical Abstracts nomenclature and refer to the position of the substituents on a ring moiety, more in particular on the dioxolane ring in the compounds of formula (I). For instance, when establishing the cis or trans configuration of the dioxolane ring in a radical of formula (D1), the substituent with the highest priority on the carbon atom in the 2 position of the dioxolane ring, and the substituent with the highest priority on the carbon atom in the 4 position of the dioxolane ring are considered (the priority of a substituent being determined according to the Cahn-Ingold-Prelog sequence rules). When said two substituents with highest priority are at the same side of the ring then the configuration is designated cis, if not, the configuration is designated trans.
The compounds of formula (I) all contain at least 2 asymmetric centers which may have the R- or S-configuration. As used herein, the stereochemical descriptors denoting the stereochemical configuration of each of the 2 or more asymmetric centers are also in accordance with Chemical Abstracts nomenclature. For instance, the absolute configuration of the asymmetric carbon atoms of compound 86, i.e. [2S-[2xcex1,4xcex1[(R*,S*)(S*)]]]-4-[4-[4-[4-[[2-(2,4-difluoropheny)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one, is as depicted hereinbelow. The dioxolane ring in this compound has the cis configuration. 
Ring numbering on the dioxolane ring according to the Chemical Abstracts nomenclature is given for radicals D1 and D2 just below. 
Of some compounds of formula (I) and of intermediates used in their preparation, the absolute stereochemical configuration was not experimentally determined. In those cases the stereoisomeric form which was first isolated is designated as xe2x80x9cAxe2x80x9d, the second as xe2x80x9cBxe2x80x9d and if more stereogenic forms are present the third xe2x80x9cCxe2x80x9d, the fourth xe2x80x9cDxe2x80x9d and so on, without further reference to the actual stereochemical configuration. However, stereogenic forms denominated xe2x80x9cAxe2x80x9d, xe2x80x9cBxe2x80x9d, xe2x80x9cCxe2x80x9d, xe2x80x9cDxe2x80x9d and so on can be unambiguously characterized. For instance, in case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d have an enantiomeric relationship, they can be unambiguously characterized by their optical rotation. A person skilled in the art is able to determine the absolute configuration of such compounds using art-known methods such as, for example, X-ray diffraction. In case xe2x80x9cAxe2x80x9d and xe2x80x9cBxe2x80x9d are stereoisomeric mixtures, they can be further separated whereby the respective first fractions isolated are designated xe2x80x9cA1xe2x80x9d and xe2x80x9cB1xe2x80x9d and the second as xe2x80x9cA2xe2x80x9d and xe2x80x9cB2xe2x80x9d, without further reference to the actual stereochemical configuration.
The N-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called N-oxide.
Whenever used hereinafter, the term xe2x80x9ccompounds of formula (I)xe2x80x9d is meant to also include their N-oxide forms, their pharmaceutically acceptable addition salts, and their stereochemically isomeric forms.
Within the scope of the present invention, R6 and R7 each independently are suitably hydrogen or methyl; or taken together form xe2x80x94R6xe2x80x94R7xe2x80x94 which suitably is a radical of formula (i) to (iv) optionally substituted with C1-4alkyl.
D is suitably a radical of formula D1.
X is suitably N.
R2 is suitably hydrogen, methyl or ethyl.
R4 and R5 suitably are identical, preferably chloro or fluoro. In particular, both R4 and R5 are fluoro.
Aryl is suitably phenyl, 1,2,3,4-tetrahydro-naphtalenyl, naphtalenyl or indanyl, said aryl optionally substituted with one or more substituents selected from halo, C1-4alkyloxy, hydroxyC1-4alkyl, C1-4alkyloxyC1-4alkyl, hydroxy, aminoC1-4alkyl and mono- or di(C1-4alkyl)aminoC1-4alkyl.
Het1 is suitably a monocyclic heterocyclic radical; preferably, pyridinyl, piperidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, furanyl, tetrahydrofuranyl or thienyl, each of said monocyclic heterocycles may optionally be substituted with one or where possible more substituents selected from halo, C1-4alkyl, hydroxy, C1-4alkyloxy, nitro, amino, trifluoromethyl, hydroxyC1-4alkyl, C1-4alkyloxy-C1-4alkyl, aminoC1-4alkyl, mono- or di(C1-4alkyl)amino-C1-4alkyl; more preferably pyridinyl, piperidinyl or tetrahydrofuranyl.
Het1 may also be suitably chromanyl.
An interesting group of compounds within the present invention are those compounds of formula (I) wherein L represents a radical of formula (a), (b) or (c), especially a radical of formula (a).
Another interesting group are those compounds of formula (I) wherein Alk is C1-6alkanediyl; particularly, 1,2-ethanediyl, 1,2-propanediyl, 2,3-propanediyl, 1,2-butanediyl, 3,4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl and 3,4-pentanediyl; especially 2,3-butanediyl.
Yet another interesting group contains those compounds of formula (I) wherein
R1 represents hydrogen, aryl, Het1, or C1-6alkyl optionally substituted with one, two or three substituents each independently selected from halo, hydroxy, C1-4alkyloxy, aryloxy, arylC1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, C1-4alkyloxycarbonylamino, C1-4alkyloxycarbonyl, aminocarbonyl, aryl or Het2;
R2 represents hydrogen or C1-6alkyl; or
in case R1 and R2 are attached to the same nitrogen atom, they may also be taken together to form a heterocyclic radical selected from morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C1-4alkyl, aryl, arylC1-4alkyl, hydroxyC1-4alkyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl or C1-4alkyloxycarbonylamino; or they may also be taken together to form an azido radical.
Particular compounds are those compounds of formula (I) wherein R6 and R7 are taken together to form xe2x80x94R6xe2x80x94R7xe2x80x94 which is a radical of formula (ii) or (iii) and D is a radical of formula D1 or D2 wherein R4 and R5 both are chloro or fluoro and X is N; more in particular, a radical of formula D1 or D2 wherein the dioxolane ring has a cis configuration.
Other particular compounds are those compounds of formula (I) wherein L represents a radical of formula (a) wherein R2 is hydrogen, methyl or ethyl; and R1 represents hydrogen, aryl, Het1 or C1-6alkyl optionally substituted with one, two or three substituents each independently selected from hydroxy, C1-4alkyloxy, aryloxy, arylC1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, aminocarbonyl, C1-4alkyloxycarbonyl, C1-4alkyloxycarbonylamino, aryl or Het2; or
R1 and R2 taken together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C1-4alkyl, aryl, arylC1-4alkyl, hydroxyC1-4alkyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl or C1-4alkyloxycarbonylamino; or
R1 and R2 taken together with the nitrogen atom to which they are attached form an azido radical.
Yet other particular compounds are those compounds of formula (I) wherein L represents a radical of formula (a), (e) or (f), especially a radical of formula (a), wherein R1 represents aryl, Het1, or C1-6alkyl substituted with at least one of the substituents selected from aryloxy, arylthio, arylC1-4alkyloxy, arylC1-4alkylthio, mono- or di(aryl)amino, mono- or di(arylC1-4alkyl)amino, benzyloxycarbonylamino, aryl or Het2; more in particular, wherein R1 represents aryl or C1-6alkyl substituted with at least one of the substituents selected from aryloxy, arylC1-4alkyloxy, mono- or di(arylC1-4alkyl)amino, aryl or Het2.
A preferred group of compounds contains those compounds of formula (I) wherein R6 and R7 are taken together to form xe2x80x94R6xe2x80x94R7xe2x80x94 which is a radical of formula (ii) or (iii); D is a radical of formula D1 or D2 wherein R4 and R5 both are fluoro and X is N; and L represents a radical of formula (a) wherein R2 is hydrogen or methyl and R1 represents hydrogen, aryl, Het1 or C1-6alkyl optionally substituted with one, two or three substituents each independently selected from hydroxy, C1-4alkyloxy, aryloxy, arylC1-4alkyloxy, cyano, amino, mono- or di(C1-4alkyl)amino, mono- or di(arylC1-4alkyl)amino, aminocarbonyl, C1-4alkyloxycarbonyl, C1-4alkyloxycarbonylamino, aryl or Het2; or
R1 and R2 taken together with the nitrogen atom to which they are attached form a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl; said heterocyclic radical may optionally be substituted with C1-4alkyl, aryl, arylC1-4alkyl, hydroxyC1-4alkyl, amino, mono- or di(C1-4alkyl)amino, mono- or di(C1-4alkyl)aminoC1-4alkyl or C1-4alkyloxycarbonylamino.
Another preferred group of compounds are those compounds of formula (I) wherein R6 and R7 are other than hydrogen, said group is represented by compounds of formula (Ixe2x80x2).
A particularly preferred group of compounds comprises those compounds of formula (I) wherein L is a radical of formula 
wherein
Alk is as defined above but preferably is 1,2-ethanediyl, 1,2-propanediyl, 2,3-propanediyl, 1,2-butanediyl, 3,4-butanediyl, 2,3-butanediyl, 2,3-pentanediyl or 3,4-pentanediyl;
Z1 is aryl, arylmethyl, arylethyl, Het1 or C1-4alkyl but preferably is optionally substituted phenyl or optionally substituted phenylmethyl, isopropyl or tert-butyl;
Z2 is hydrogen, carboxyl, C1-4alkyloxycarbonyl, aminocarbonyl or methyl optionally substituted with hydroxy, methoxy, amino or mono- or di(methyl)amino but preferably is hydrogen, methyl or hydroxymethyl;
or Z1 and Z2 taken together with the carbon atom to which they are attached form a piperidinyl ring substituted with arylmethyl, arylethyl or C1-4alkyl;
Z3 is O, Nxe2x80x94C1-4alkyl or N-aryl.
Most preferred are the compounds:
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxlan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(2-phenylethyl)amino]1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-(4-phenyl-1-piperazinyl)methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(3-phenylpropyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2-[2-[[(2-fluorophenyl)methyl]amino]-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4,-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[(2-methoxyphenyl)-methyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(2-phenoxyethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(2,3-dihydro-1H-inden-2-yl)amino]-1-methylpropyl]-3H-1,2,4,-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1-H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2-[2-[[1-(4-fluorophenyl)ethyl]amino]-1-methylpropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(phenylmethyl)-4-piperidinyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-(4-morpholinyl)-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(hydroxymethyl)-2-phenylethyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(2-hydroxy-1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[2-(2-hydroxy-2-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(hydroxymethyl)-2-methylpropyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[1-(1-phenylethyl)-4-piperidinyl]-3H-1,2,4-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-dichlorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(hydroxymethyl)-2-methylpropyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
2-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]-methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-4-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4,-triazol-3-one;
4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[4-[(phenylmethyl)amino]-cyclohexyl]-3H-1,2,4-triazol-3-one; the N-oxide forms, the pharmaceutically acceptable addition salts and stereochemically isomeric forms thereof.
Most preferred stereochemically pure compounds are
[2S-[2xcex1,4xcex1[(R*,S*)(S*)]]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(1-phenylethyl)amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one;
[2S-[2xcex1,4xcex1(S*,R*)]]4-[4-[4-[4-[[2,4-diflourophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[(phenylmethyl)amino]-1-methylpropyl]-3H-1,2,4,-triazol-3-one; and
[2S-[2xcex1,4xcex1[(R*,S*)(R*)]]]-4-[4-[4-[4-[[2-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)-1,3-dioxolan-4-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-2-[2-[[1-(hydroxymethyl)-2-methylpropyl]amino]-1-methylpropyl]-3H-1,2,4-triazol-3-one.
The compounds of the present invention wherein R6 and R7 are other than hydrogen, said R6 and R7 being represented by R6 and R7 and said compounds being represented by formula (Ixe2x80x2), can be prepared by reacting an intermediate of formula (II) wherein W1 is a suitable leaving group such as, for example, a halogen, e.g. iodo, an arylsulfonyloxy or an alkanesulfonyloxy group, e.g. p-toluenesulfonyloxy, naphtylsulfonyloxy or methanesulfonyloxy, with an intermediate of formula (III) in a reaction-inert solvent such as, for example, N,N-dimethylformamide, N,N-dimethyl-acetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, sulfolane or the like, and in the presence of a suitable base such as, for example, sodiumhydroxide or sodiumhydride. 
In this and the following preparations, the reaction products may be isolated from the reaction medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. In particular, stereoisomers can be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak AD (amylose 3,5 dimethylphenyl carbamate) or Chiralpak AS, both purchased from Daicel Chemical Industries, Ltd, in Japan.
Compounds of formula (Ixe2x80x2) may also be prepared by N-alkylating an intermediate of formula (IV) with an intermediate of formula (V) wherein W2 is a suitable leaving group such as, for example, a halogen, and wherein reactive amino groups in L such as primary and secondary amines, in case they are present, are protected with a protective group P such as, for example, a C1-4alkyloxycarbonyl group, in a reaction-inert solvent such as, for example, dimethylsulfoxide, in the presence of a base such as, for example, potassium hydroxide. In case L was protected, art-known deprotection techniques can be employed to arrive at compounds of formula (Ixe2x80x2) after the N-alkylation reation. 
Compounds of formula (Ixe2x80x2) wherein L is a radical of formula (a), said compounds being represented by formula (Ixe2x80x2-a), may be prepared by reacting an intermediate of formula (VI) wherein W3 is a suitable leaving group such as, for example, a halogen, an arylsulfonyloxy or an alkanesulfonyloxy group, e.g. p-toluenesulfonyloxy, naphtylsulfonyloxy or methanesulfonyloxy, with an intermediate of formula (VII) optionally in the presence of a suitable base such as, for example, sodium- or potassium carbonate, triethylamine or the like, and optionally in a reaction-inert solvent such as, for example, N,N-dimethylformamide, N,N-dimethyl-acetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-2-imidazolidinone, sulfolane or the like. In case R1 and R2 form together with the nitrogen atom to which they are attached an azido radical, NaN3 may be used as intermediate of formula (VII). 
The compounds of formula (I) wherein at least one of R6 or R7 is hydrogen, said R6 and R7 being represented by R6xe2x80x3 and R7xe2x80x3 and said compounds being represented by formula (Ixe2x80x3), can be prepared following the reaction procedure in scheme 1. 
In scheme 1, the intermediates of formula (VIII-a) wherein NP2 is a protected amino group wherein P is for example a C1alkyloxycarbonyl group, or a functional derivative of NP2 such as, for example, a nitro group, are reacted with an intermediate of formula (II) according to the procedure described for the preparation of compounds of formula (Ixe2x80x2). The thus obtained intermediates of formula (VIII-b) may be deprotected according to art-known deprotection techniques, thus obtaining an amine derivative of formula (VIII-c). In case NP2 is a nitro group, art-known reduction techniques may be used to obtain amines of formula (VIII-c). The amine derivatives of formula (VIII-c) can then be reacted with phenyl chloroformate or a functional derivative thereof. In order to obtain compounds of formula (Ixe2x80x3) wherein R6xe2x80x3 is C1-4alkyl, amine derivatives of formula (VII-c) may first be reacted with C1-4alkyl-W4 wherein W4 is a suitable leaving group such as, for example, a halogen, and then reacted with phenyl chloroformate.
The thus obtained intermediates of formula (VIII-e) may be reacted with an intermediate of formula (IX) wherein reactive amino groups in L such as primary and secondary amines, in case they are present, are protected with a protective group P such as, for example, a C1-4alkyloxycarbonyl group. Suitably, the reactive amino group may then be deprotected using art-known deprotection techniques to arrive at the desired compound of formula (Ixe2x80x3).
The compounds of formula (I) may also be converted into each other following art-known transformations.
For instance, compounds of formula (Ixe2x80x2) wherein L is a radical of formula (b), said compounds being represented by formula (Ixe2x80x2-b), may be prepared using art-known acylation methods e.g., those described in xe2x80x9cPrinciples of Peptide Synthesisxe2x80x9d, M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984.
A particular acylation procedure involves the acylation of a compound of formula (Ixe2x80x2-a) wherein R1 is hydrogen, said compounds being represented by formula (Ixe2x80x2-a-1), with an intermediate of formula (X-b) wherein W5 is a suitable leaving group such as, for example, a halogen or a hydroxy group, in the presence of a suitable base such as, for example, sodiumbicarbonate or N,N-dimethylaminopyridine or a functional derivative thereof, and in a reaction-inert solvent such as, for example, dichloromethane, dichloroethane, tetrahydrofuran or the like. 
In case W5 is hydroxy, it may be convenient to activate the carboxylic acid of formula (X-b) by adding a diimide such as, for example, N,Nxe2x80x2dicyclohexylcarbodiimide; 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide or a functional derivative thereof. Alternatively, the carboxylic acid of formula (X-b) may be activated by adding carbonyldiimidazole or a functional derivative thereof.
In case an chirally pure intermediate of formula (X-b) is used, fast and enantiomerization-free couplings may be performed by adding hydroxybenzotriazole, benzotriazolyloxytris(dimethylamino) phosphonium hexafluorophosphate, tetrapyrrolidinophosphonium hexafluorophosphate, bromotripyrrolidinophosphonium hexafluorophosphate or a functional derivative thereof (D. Hudson, J. Org. Chem., 1988, 53, p617 and 1999 Novabiochem catalogue and peptide Synthesis Handbook).
An analogous acylation procedure as for the preparation of compounds of formula (Ixe2x80x2-b) may be used for the preparation of compounds of formula (Ixe2x80x2) wherein L is a radical of formula (c), said compounds being represented by formula (Ixe2x80x2-c). In said analogous reaction procedure, the intermediate of formula (X-b) is replaced by a carbonate of formula C1-4alkylxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R1 (X-c-1), a chloroformate of formula Clxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94R1 (X-c-2) or C1-4alkyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C1-4alkyl (X-c-3).
An analogous acylation procedure as for the preparation of compounds of formula (Ixe2x80x2-b) may be used for the preparation of compounds of formula (Ixe2x80x2) wherein L is a radical of formula (d), said compounds being represented by formula (Ixe2x80x2-d). In said analogous reaction procedure, the intermediate of formula (X-b) is replaced by an isocyanate of formula Oxe2x95x90Cxe2x95x90Nxe2x80x94R1 (X-d-1), an isothiocyanate of formula Sxe2x95x90Cxe2x95x90Nxe2x80x94R1 (X-d-2), a phenylcarbamate of formula phenyl-Oxe2x80x94C(xe2x95x90O)xe2x80x94NR1R2 (X-d-3), a phenylthiocarbamate of formula phenyl-Oxe2x80x94C(xe2x95x90S)xe2x80x94NR1R2 (X-d4), or an intermediate of formula C1-4alkyl-Sxe2x80x94C(xe2x95x90NR2)xe2x80x94NR1R2 (X-d-5).
Compounds of formula (Ixe2x80x2-a-1) may also be reductively N-alkylated with an aldehyde or keton of formula R1aC(xe2x95x90O)R1b (XI) wherein R1a and R1b are so defined that the radical xe2x80x94CHR1aR1b is encompassed by the definition of R1, thus forming compounds of formula (Ixe2x80x2-a-2). Said reductive N-alkylation may be performed in a reaction-inert solvent such as, for example, toluene, methanol, tetrahydrofuran or a mixture thereof, and in the presence of a reducing agent such as, for example, a borohydride, e.g. sodium borohydride, zinc borohydride, lithium borohydride, sodium cyanoborohydride or triacetoxy borohydride. In case a borohydride is used as a reducing agent, it may be convenient to use a catalyst such as, for example, titanium(IV) isopropoxide as described in J. Org. Chem, 1990, 55, 2552-2554. It may also be convenient to use hydrogen as a reducing agent in combination with a suitable catalyst such as, for example, palladium-on-charcoal or platinum-on-charcoal. The formation of a Schiff base in the first step of the reductive N-alkylation can be enhanced by the addition of a suitable reagent to the reaction mixture such as, for example, aluminium tert-butoxide, calcium oxide, calcium hydride or a titanium(IV)alkoxide, e.g. titanium(IV)isopropoxide or titanium(IV)-n-butoxide. An appropriate catalyst-poison, e.g., thiophene, butanethiol or quinoline-sulphur, may also be added to the reaction mixture to prevent the undesired further hydrogenation of certain functional groups in the reactants and the reaction products. Stirring and optionally elevated temperatures and/or pressure may enhance the rate of the reaction. 
Compounds of formula (Ixe2x80x2) wherein L is a radical of formula (a) and R1 is xe2x80x94CH2xe2x80x94CH(OH)substituent wherein the substituent belongs to the group of substituents of C1-4alkyl in the definition of R1, said compounds being represented by formula (Ixe2x80x2-a-3), may be prepared by reacting an intermediate of formula (Ixe2x80x2-a-1) with an epoxide of formula (XII) in a reaction-inert solvent such as, for example, 2-propanol. 
Compounds of formula (I) containing a C1-4alkyloxycarbonylamino moiety may be converted to compounds of formula (I) containing the corresponding amino moiety using art-known techniques such as, for example, reaction in dichloromethane and in the presence of trifluoroacetic acid.
Compounds of formula (Ixe2x80x2) containing a primary amine may be mono-methylated by first protecting the primary amine with a suitable protecting group such as, for example, an arylalkyl group, e.g. benzyl, and subsequently methylating the secondary amine using art-known methylation techniques such as, for example, reaction with paraformaldehyde. The thus obtained tertiary amine may be deprotected using art-known deprotection techniques such as, for example, reaction with hydrogen in tetrahydrofuran or methanol and in the presence of a catalyst such as, for example palladium-on-charcoal, thus obtaining the desired methylated secondary amine.
The compounds of formula (I) may also be converted to the corresponding N-oxide forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said N-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents.
Some of the intermediates and starting materials used in the above reaction procedures are commercially available, or may be synthesized according to procedures described elsewhere, e.g. U.S. Pat. Nos. 4,791,111, 4,931,444 and 4,267,179. Some methods of preparing the intermediates of the present invention are described hereinbelow.
For instance, intermediates of formula (III) wherein L is a radical of formula (a), said intermediates being represented by formula (III-a), can be prepared by reductively aminating a carbonyl containing intermediate of formula (XIII) wherein Alkxe2x95x90O is the same as Alk substituted with an oxo group, with an intermediate of formula (VII) following the same reaction procedures as described for the reductive N-alkylation of compounds of formula (Ixe2x80x2-a-1) with intermediates of formula (XI). 
The above reaction procedure may be performed with chirally pure starting materials, employing stereoselective reaction procedures, thus obtaining chirally pure intermediates of formula (III-a). For instance, an stereoselective reductive amination of a chirally pure form of an intermediate of formula (XIII) with a chirally pure form of formula (VII) may be a reaction using hydrogen on palladium-on-charcoal as reducing agent in the presence of a thiophene solution and titanium(IV) isopropoxide. The resulting stereoisomeric forms may be separated using chromatographic or other art-known techniques.
It may also be convenient to perform the above reaction on the alkylphenoxy derivatives of the intermediates of formula (XIII).
Intermediates of formula (III-a) wherein R1 is an arylC1-6alkyl group may be reduced using art-known reduction techniques such as, for example, a reduction with hydrogen in the presence of palladium on activated charcoal, thus obtaining intermediates of formula (III-a) wherein R1 is hydrogen, said intermediates being represented by formula (III-a-1). 
Said intermediates of formula (III-a-1) may be converted to intermediates of formula (III) wherein L is a radical of formula (b), (c) or (d), being represented by formula (III-b), (III-c) and (III-d) respectively, using art-known acylation methods e.g., those described in xe2x80x9cPrinciples of Peptide Synthesisxe2x80x9d, M. Bodanszky, Springer-Verlag Berlin Heidelberg, 1984 and 1999 Novabiochem Catalogue and Peptide Synthesis Handbook.
Also, amides of formula (III-b) may be hydrolysed using a suitable acid such as, for example hydrochloric acid, thus obtaining intermediates of formula (III-a-1).
Pure stereoisomeric forms of the compounds and the intermediates of this invention may be obtained by the application of art-known procedures. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography using chiral stationary phases. Enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromato-graphic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereo-selectively or stereospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chirally pure starting materials. Stereoisomeric forms of the compounds of formula (I) are obviously intended to be included within the scope of the invention.
The chirally pure forms of the compounds of formula (I) form a preferred group of compounds. It is therefore that the chirally pure forms of the intermediates of formula (II), (III) and (VI), their N-oxide forms and their addition salt forms are particularly useful in the preparation of chirally pure compounds of formula (I). Also enantiomeric mixtures and diastereomeric mixtures of intermediates of formula (II), (III) and (VI) are useful in the preparation of compounds of formula (I) with the corresponding configuration. Said chirally pure forms and also the enantiomeric and diastereomeric mixtures of the intermediates of formula (III) are deemed novel.
A specific way to stereoselectively prepare intermediates of formula (III-a) wherein R1 and R2 are hydrogen and Alk is xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94 wherein both asymmetric carbon atoms have the S-configuration, being represented by formula (SS)(III-a-2), or the alkoxyphenyl analogues thereof, is as depicted in scheme 2a. 
The reaction of an intermediate of formula (XIV) with (4R-trans)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathiolane may be performed in a suitable solvent, preferably a polar aprotic solvent such as, for example, dimethylacetamide or N,N-dimethylformamide, and in the presence of a base such as, for example, potassium tert-butanolate, potassium hydroxide or potassium hydride. Subsequently, an acid such as, sulfuric acid, may be added to the reaction mixture, thus obtaining an intermediate of formula (SR)(XV) whereby the 2-hydroxy-1-methylpropyl moiety has the erythro form. Then, the carbon atom bearing the alcohol function of said 2-hydroxy-1-methylpropyl moiety is epimerized, preferably 100% inverted, thus obtaining intermediate (SS)(XVII) whereby the 2-amino-1-methylpropyl moiety has the threo form. Two pathways are convenient.
A first pathway involves the transformation of the alcohol function into a suitable leaving group O-LG by, for instance, derivatizing the hydroxy group with an organic acid such as, for example, a sulfonic acid, e.g. p-toluenesulfonic acid or methane-sulfonic acid; thus obtaining an intermediate of formula (SR)(XVI). The carbon atom bearing the leaving group in said intermediate (SR)(XVI) may subsequently be epimerized, preferably 100% inverted, by a SN2-type reaction with a suitable nucleophilic reagent such as, for example, NaN3, which may subsequently be reduced to the primary amine of formula (SS)(XVII). Alternatively, the Gabriel synthesis, its Ing-Manske modification or another functional modification thereof may be employed to prepare a primary amine of formula (SS)(XVII).
An alternative pathway for inverting the stereochemistry of the carbon atom bearing the alcohol function is the use of the Mitsunobu reaction. The alcohol function of an intermediate of formula (SR)(XV) is activated with diisopropyl azodicarboxylate or a functional derivative thereof such as diethyl azodicarboxylate, in the presence of triphenylphosphine, and in a polar aprotic solvent such as, for example, dimethyl-acetamide or dimethylformamide. The thus obtained activated alcohol is subsequently reacted with an amide such as, for example, 2,2,2-trifluoroacetamide or a functional derivative thereof. The thus obtained amide whereby the 2-hydroxy-1-methylpropyl moiety has been transformed to the threo form may subsequently be hydrolysed using art-known hydrolysis techniques, thus obtaining an intermediate of formula (SS)(XVII).
In order to obtain intermediates of formula (SR)(XVII), an additional inversion step can be introduced as is depicted in scheme 2b. 
The intermediates of formula (SR)(XV) is converted to an intermediate of formula (SS)(XV) using two possible pathways. A first one involves the transformation of the alcohol function into a suitable leaving group O-LG as described hereinabove; thus obtaining an intermediate of formula (SR)(XVI). The carbon atom bearing the leaving group in said intermediate (SR)(XVI) may subsequently be epimerized, preferably 100% inverted, by a SN2-type reaction with a suitable nucleophilic reagent such as, for example, a alcoholate, e.g. a benzyloxy group; an hydroxy salt of an alkali metal, e.g. sodiumhydroxide or potassium hydroxide; an acetate, e.g. sodium acetate. Said reaction is performed in a suitable solvent, preferably a polar aprotic solvent such as, for example, dimethylacetamide, N-methylpyrrolidinone, dimethylimidazolidinone or sulfolane. In case an alcoholate or an acetate is used in the SN2 reaction, the thus obtained intermediate may be deprotected using art-known deprotection techniques, thus obtaining an alcohol intermediate of formula (SS)(XV).
Another pathway involves the Mitsunobu reaction. The alcohol function of an intermediate of formula (SR)(XV) is activated as described hereinabove. The thus obtained activated alcohol is subsequently reacted with a carboxylic acid such as, for example, 4-nitrobenzoic acid, acetic acid, monochloroacetic acid. The thus obtained ester may subsequently be hydrolysed using art-known hydrolysis techniques, thus obtaining an intermediate of formula (SS)(XV).
The intermediates of formula (SS)(XV) may then be reacted to obtain intermediates of formula (SR)(XVII) using the same reaction pathways as described for the preparation of intermediates (SS)(XVII) starting from (SR)(XV).
Finally, the alkoxyphenyl moiety of the intermediates of formula (SS)(XVII) or (SR)(XVII) may be transformed to the phenol moiety using for instance, hydrobromic acid, or a mixture of hydrobromic acid and hydrobromic acid in acetic acid, in the presence of NaHSO3, thus obtaining an intermediate of formula (SS)(III-a-2) or (SR)(III-a-2).
Suitable alternatives for (4R-trans)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathiolane include the following chirally pure intermediates: 
wherein LG is a leaving group such as, for example, p-toluenesulfonyl.
The intermediates of formula (III-a-2), whereby the 2-hydroxy-1-methylpropyl moiety has the [Rxe2x80x94(R*,R*)] form, said intermediates being represented by (RR)(III-a-2), may be prepared using the same reaction pathways as depicted in scheme 2 but replacing (4R-trans)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathiolane with its enantiomer (4S-trans)-4,5-dimethyl-2,2-dioxide-1,3,2-dioxathiolane.
Intermediates of formula (VI) can be prepared by reducing an intermediate of formula (XIII) and subsequently introducing a leaving group W3. In particular, intermediates of formula (VI) wherein Alk is xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94, said intermediates being represented by formula (VI-a), may be prepared according to the reaction scheme as depicted in scheme 3. Optionally, the chirally pure intermediates of formula (VI-a), represented by (SS)(VI-a), (SR)(VI-a), (RS)(VI-a) and (RR)(VI-a), can be prepared using this procedure. 
Suitable stereoselective reduction conditions include the use of K-selectride in a suitable solvent such as, for example, dimethylacetamide or tetrahydrofuran; the use of sodiumborohydride optionally in combination with CeCl3.7H2O, ZnCl2 or CaCl2.2H2O in a suitable solvent such as, for example, dimethylacetamide, dimethylformamide, methanol or tetrahydrofuran. Said reduction conditions favour the threo form of the 2-hydroxy-1-methylpropyl moiety, i.e. the form where the two asymmetric carbon atoms have identical absolute configuration. Recrystallisation of the obtained intermediate of formula (XVIII) after stereoselective reduction may even further improve the ratio threo/erythro in favor of the threo form. The desired stereoisomeric forms of the intermediates of formula (XVIII), being (RR)(XVIII), (SS)(XVIII), (RS)(XVIII) and (SR)(XVIII), can then optionally be isolated chromatographically using a chiral stationary phase such as, for example, Chiralpak AD (amylose 3,5-dimethylphenyl carbamate) purchased from Daicel Chemical Industries, Ltd, in Japan. The intermediate of formula (XVIII) or one or more of its stereoisomeric forms, may then be further reacted with an intermediate of formula (II) as described hereinabove for the general preparation of compounds of formula (Ixe2x80x2). Finally, the hydroxy group of the thus obtained intermediates of formula (XIX) or a chirally pure form thereof, may be transformed into a suitable leaving group W3 by, for instance, derivatizing the hydroxy group with an organic acid such as, for example, a sulfonic acid, e.g. p-toluenesulfonic acid or methanesulfonic acid; thus obtaining an intermediate of formula (VI-a) or a chirally pure form thereof.
The compounds of formula (I), the pharmaceutically acceptable addition salts and the stereochemically isomeric forms thereof are useful agents for combating fungi in vivo. The present compounds are broad-spectrum antifungals. They are active against a wide variety of fungi, such as Candida spp., e.g. Candida albicans, Candida glabrata, Candida krusei, Candida parapsilosis, Candida kefyr, Candida tropicalis; Aspergillus spp., e.g. Aspergillus fumigatus, Aspergillus niger, Aspergillus flavus; Cryptococcus neoformans; Sporothrix schenckii; Fonsecaea spp.; Epidermophyton floccosum; Microsporum canis; Trichophyton spp.; Fusarium spp.; and several dematiaceous hyphomycetes. Of particular interest is the improved activity of some of the present compounds against Fusarium spp.
In vitro experiments, including the determination of the fungal susceptibility of the present compounds as described in the pharmacological example hereinafter, indicate that the compounds of formula (I) have a favourable intrinsic inhibitory capacity on fungal growth in for instance Candida albicans. Other in vitro experiments such as the determination of the effects of the present compounds on the sterol synthesis in, for instance, Candida albicans, also demonstrate their antifungal potency. Also in vivo experiments in several mouse, guinea-pig and rat models show that, after both oral and intravenous administration, the present compounds are potent antifungals.
An additional advantage of some of the present compounds is that they are not only fungistatic, as most of the known azole antifungals, but are also fungicidal at acceptable therapeutic doses against many fungal isolates.
The compounds of the present invention are chemically stable and have a good oral availability.
The solubility profile in aqueous solutions of the compounds of formula (I) makes them suitable for intravenous administration. Particularly interesting compounds are those compounds of formula (I) having a water-solubility of at least 0.1 mg/ml at a pH of at least 4, preferably, a water-solubility of at least 1 mg/ml at a pH of at least 4, and more preferred a water-solubility of 5 mg/ml at a pH of at least 4.
In view of the utility of the compounds of formula (I), there is provided a method of treating warm-blooded animals, including humans, suffering from fungal infections. Said method comprises the systemic or topical administration of an effective amount of a compound of formula (I), a N-oxide form, a pharmaceutically acceptable addition salt or a possible stereoisomeric form thereof, to warm-blooded animals, including humans. Hence, compounds of formula (I) are provided for use as a medicine, in particular, the use of a compound of formula (I) in the manufacture of a medicament useful in treating fungal infections is provided.
The present invention also provides compositions for treating or preventing fungal infections comprising a therapeutically effective amount of a compound of formula (I) and a pharmaceutically acceptable carrier or diluent.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of this invention, a therapeutically effective amount of a particular compound, in base or addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, topically, percutaneously, transungually or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. As appropriate compositions for topical application there may be cited all compositions usually employed for topically administering drugs e.g. creams, gel, dressings, shampoos, tinctures, pastes, ointments, salves, powders and the like. In the compositions suitable for percutaneous administration, the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be helpful for preparing the desired compositions. These compositions may be administered in various ways, e.g., as a transdermal patch, as a spot-on, as an ointment.
Transungual compositions are in the form of a solution and the carrier optionally comprises a penetration enhancing agent which favours the penetration of the antifungal into and through the keratinized ungual layer of the nail. The solvent medium comprises water mixed with a co-solvent such as an alcohol having from 2 to 6 carbon atoms, e.g. ethanol.
For parenteral compositions, the carrier will usually comprise sterile water, at least in large part. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. For parenteral compositions, other ingredients, to aid solubility for example, e.g. cyclodextrins, may be included.
Appropriate cyclodextrins are xcex1-, xcex2-, xcex3-cyclodextrins or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with C1-6alkyl, particularly methyl, ethyl or isopropyl, e.g. randomly methylated xcex2-CD; hydroxyC1-6alkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyC1-6alkyl, particularly carboxymethyl or carboxyethyl; C1-6alkylcarbonyl, particularly acetyl. Especially noteworthy as complexants and/or solubilizers are xcex2-CD, randomly methylated xcex2-CD, 2,6-dimethyl-xcex2-CD, 2-hydroxyethyl-xcex2-CD, 2-hydroxyethyl-xcex3-CD, 2-hydroxypropyl-xcex3-CD and (2-carboxymethoxy)propyl-xcex2-CD, and in particular 2-hydroxypropyl-xcex2-CD (2-HP-xcex2-CD).
The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl.
The average molar substitution (M.S.) is used as a measure of the average number of moles of alkoxy units per mole of anhydroglucose. The average substitution degree (D.S.) refers to the average number of substituted hydroxyls per anhydroglucose unit. The M.S. and D.S. value can be determined by various analytical techniques such as nuclear magnetic resonance (NMR), mass spectrometry (MS) and infrared spectroscopy (IR). Depending on the technique used, slightly different values may be obtained for one given cyclodextrin derivative. Preferably, as measured by mass spectrometry, the M.S. ranges from 0.125 to 10 and the D.S. ranges from 0.125 to 3.
Other suitable compositions for oral or rectal administration comprise particles obtainable by melt-extruding a mixture comprising a compound of formula (I) and an appropriate water-soluble polymer and subsequently milling said melt-extruded mixture. Said particles can then be formulated by conventional techniques into pharmaceutical dosage forms such as tablets and capsules.
Said particles consist of a solid dispersion comprising a compound of formula (I) and one or more pharmaceutically acceptable water-soluble polymers. The preferred technique for preparing solid dispersions is the melt-extrusion process comprises the following steps:
a) mixing a compound of formula (I) and an appropriate water-soluble polymer,
b) optionally blending additives with the thus obtained mixture,
c) heating the thus obtained blend until one obtains a homogenous melt,
d) forcing the thus obtained melt through one or more nozzles; and
e) cooling the melt till it solidifies.
The solid dispersion product is milled or ground to particles having a particle size of less than 600 xcexcm, preferably less than 400 xcexcm and most preferably less than 125 xcexcm.
The water-soluble polymers in the particles are polymers that have an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2% aqueous solution at 20xc2x0 C. solution. For example, suitable water-soluble polymers include alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkyl alkylcelluloses, carboxyalkylcelluloses, alkali metal salts of carboxyalkylcelluloses, carboxyalkylalkylcelluloses, carboxyalkylcellulose esters, starches, pectines, chitin derivates, polysaccharides, polyacrylic acids and the salts thereof, polymethacrylic acids and the salts thereof, methacrylate copolymers, polyvinylalcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, polyalkylene oxides and copolymers of ethylene oxide and propylene oxide. Preferred water-soluble polymers are hydroxypropyl methylcelluloses.
Also one or more cyclodextrins can be used as water soluble polymer in the preparation of the above-mentioned particles as is disclosed in WO 97/18839. Said cyclodextrins include the pharmaceutically acceptable unsubstituted and substituted cyclodextrins known in the art, more particularly xcex1, xcex2 or xcex3 cyclodextrins or the pharmaceutically acceptable derivatives thereof.
Substituted cyclodextrins which can be used include polyethers described in U.S. Pat. No. 3,459,731. Further substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-6alkyl, hydroxyC1-6alkyl, carboxy-C1-6alkyl or C1-6alkyloxycarbonylC1-6alkyl or mixed ethers thereof. In particular such substituted cyclodextrins are ethers wherein the hydrogen of one or more cyclodextrin hydroxy groups is replaced by C1-3alkyl, hydroxyC2-4alkyl or carboxyC1-2alkyl or more in particular by methyl, ethyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, carboxy-methyl or carboxyethyl.
Of particular utility are the xcex2-cyclodextrin ethers, e.g. dimethyl-xcex2-cyclodextrin as described in Drugs of the Future, Vol. 9, No. 8, p. 577-578 by M. Nogradi (1984) and polyethers, e.g. hydroxypropyl xcex2-cyclodextrin and hydroxyethyl xcex2-cyclodextrin, being examples. Such an alkyl ether may be a methyl ether with a degree of substitution of about 0.125 to 3, e.g. about 0.3 to 2. Such a hydroxypropyl cyclodextrin may for example be formed from the reaction between xcex2-cyclodextrin an propylene oxide and may have a MS value of about 0.125 to 10, e.g. about 0.3 to 3.
A more novel type of substituted cyclodextrins is sulfobutylcyclodextrines.
The ratio of active ingredient over cyclodextrin may vary widely. For example ratios of 1/100 to 100/1 may be applied. Interesting ratios of active ingredient over cyclodextrin range from about 1/10 to 10/1. More interesting ratios of active ingredient over cyclodextrin range from about 1/5 to 5/1.
It may further be convenient to formulate the present azole antifungals in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the antifungal agent but do not chemically bond to the antifungal agent.
Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants.
Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present antifungals are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration.
Said beads comprise a central, rounded or spherical core, a coating film of a hydrophilic polymer and an antifungal agent and a seal-coating polymer layer.
Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof.
The pharmaceutical compositions mentioned above may also contain a fungicidally effective amount of other antifungal compounds such as cell wall active compounds. The term xe2x80x9ccell wall active compoundxe2x80x9d, as used herein, means any compound which interferes with the fungal cell wall and includes, but is not limited to, compounds such as papulacandins, echinocandins, and aculeacins as well as fungal cell wall inhibitors such as nikkomycins, e.g. nikkomycin K and others which are described in U.S. Pat. No. 5,006,513.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specification and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoonfuls and the like, and segregated multiples thereof.
Those of skill in treating warm-blooded animals suffering from diseases caused by fungi could easily determine the therapeutically effective daily amount from the test results given herein. In general, it is contemplated that a therapeutically effective daily amount would be from 0.05 mg/kg to 20 mg/kg body weight.